TRIM8 encodes an E3 ubiquitin ligase. Although TRIM8 variants were initially observed in cases of epileptic encephalopathy in 2013 and 2016 (PMIDs: 23934111, 27346735), the first report focusing on variants in TRIM8 as a cause of autosomal dominant focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) was published in 2018 (PMID: 30244534). To date, de novo TRIM8 variants have been reported in at least 20 individuals with FSGSNEDS (PMIDs: 23934111, 27346735, 30244534, 32193649, 32531461, 33508234). FSGSNEDS results in early-onset developmental delay (DD) and mild to severe intellectual disability in all reported patients, seizures in 19/20 reported patients, and renal manifestations (proteinuria, steroid resistant nephrotic syndrome, focal segmental glomerulosclerosis, diffuse mesangial sclerosis) in 17/20 reported patients (PMIDs: 30244534, 33508234). The reported renal manifestations may not present until later in childhood or adolescence (PMID: 33508234). To date, all reported TRIM8 variants observed in individuals with FSGSNEDS have been de novo nonsense or frameshift variants that cluster within the last exon between residues 390 and 487; these variants are expected to escape nonsense mediated decay and are hypothesized to act through gain-of-function or toxic effects (PMID: 33508234). In addition, TRIM8 constructs carrying patient-specific variants mislocalized to the nucleoplasm instead of nuclear bodies in podocytes and neuronal cells (PMID: 33508234).
In summary, the TRIM8 gene is definitively associated with autosomal dominant focal segmental glomerulosclerosis and neurodevelopmental syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 6 2021 (SOP Version 8).
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